Aciphex

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Presence Of Gastric Malignancy

Symptomatic response to therapy with rabeprazole does not
preclude the presence of gastric malignancy.

Patients with healed GERD were treated for up to 40
months with rabeprazole and monitored with serial gastric biopsies. Patients
without H. pylori infection (221 of 326 patients) had no clinically
important pathologic changes in the gastric mucosa. Patients with H. pylori
infection at baseline (105 of 326 patients) had mild or moderate inflammation
in the gastric body or mild inflammation in the gastric antrum. Patients with
mild grades of infection or inflammation in the gastric body tended to change
to moderate, whereas those graded moderate at baseline tended to remain stable.
Patients with mild grades of infection or inflammation in the gastric antrum
tended to remain stable. At baseline, 8% of patients had atrophy of glands in
the gastric body and 15% had atrophy in the gastric antrum. At endpoint, 15% of
patients had atrophy of glands in the gastric body and 11% had atrophy in the
gastric antrum. Approximately 4% of patients had intestinal metaplasia at some
point during follow-up, but no consistent changes were seen.

Concomitant Use With Warfarin

Steady state interactions of rabeprazole and warfarin have
not been adequately evaluated in patients. There have been reports of increased
INR and prothrombin time in patients receiving a proton pump inhibitor and
warfarin concomitantly. Increases in INR and prothrombin time may lead to
abnormal bleeding and even death. Patients treated with a proton pump inhibitor
and warfarin concomitantly may need to be monitored for increases in INR and
prothrombin time.

Acute Interstitial Nephritis

Acute interstitialnephritis has been observed in
patients taking PPIs including ACIPHEX. Acute interstitial nephritis may occur
at any point during PPI therapy and is generally attributed to an idiopathic
hypersensitivity reaction. Discontinue ACIPHEX if acute interstitial nephritis
develops [see CONTRAINDICATIONS].

Cyanocobalamin (vitamin B-12) Deficiency

Daily treatment with any acid-suppressing medications
over a long period of time (e.g., longer than 3 years) may lead to
malabsorption of cyanocobalamin (vitamin B-12) caused by hypo-or achlorhydria.
Rare reports of cyanocobalamin deficiency occurring with acid-suppressing
therapy have been reported in the literature. This diagnosis should be
considered if clinical symptoms consistent with cyanocobalamin deficiency are
observed.

Clostridium Difficile Associated Diarrhea

Published observational studies suggest that PPI therapy
like ACIPHEX may be associated with an increased risk of Clostridium
difficile associated diarrhea, especially in hospitalized patients. This
diagnosis should be considered for diarrhea that does not improve [seeADVERSE REACTIONS].

Patients should use the lowest dose and shortest duration
of PPI therapy appropriate to the condition being treated.

Clostridium difficile associated diarrhea (CDAD)
has been reported with use of nearly all antibacterial agents. For more
information specific to antibacterial agents (clarithromycin and amoxicillin)
indicated for use in combination with ACIPHEX, refer to WARNINGS AND PRECAUTIONS
sections of those package inserts.

Bone Fracture

Several published observational studies in adults suggest
that PPI therapy may be associated with an increased risk for
osteoporosis-related fractures of the hip, wrist, or spine. The risk of
fracture was increased in patients who received high-dose, defined as multiple
daily doses, and long-term PPI therapy (a year or longer). Patients should use
the lowest dose and shortest duration of PPI therapy appropriate to the
condition being treated. Patients at risk for osteoporosis-related fractures
should be managed according to established treatment guidelines [seeDOSAGE
AND ADMINISTRATION and ADVERSE REACTIONS].

Hypomagnesemia

Hypomagnesemia, symptomatic and asymptomatic, has been
reported rarely in patients treated with PPIs for at least three months, in
most cases after a year of therapy. Serious adverse events include tetany,
arrhythmias, and seizures. In most patients, treatment of hypomagnesemia
required magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who
take PPIs with medications such as digoxin or drugs that may cause
hypomagnesemia (e.g., diuretics), healthcare professionals may consider
monitoring magnesium levels prior to initiation of PPI treatment and
periodically [see ADVERSE REACTIONS].

Concomitant Use Of ACIPHEX With Methotrexate

Literature suggests that concomitant use of PPIs with
methotrexate (primarily at high dose; see methotrexate prescribing
information) may elevate and prolong serum levels of methotrexate and/or
its metabolite, possibly leading to methotrexate toxicities. In high-dose
methotrexate administration, a temporary withdrawal of the PPI may be
considered in some patients [see DRUG INTERACTIONS].

Patient Counseling Information

How to Take ACIPHEX

Patients should be cautioned
that ACIPHEX Delayed-Release Tablets should be swallowed whole. The tablets
should not be chewed, crushed, or split. ACIPHEX can be taken with or without
food.

ACIPHEX Sprinkle
Delayed-Release Capsules should be opened and the granule contents sprinkled on
a small amount of soft food (e.g., applesauce, fruit, or vegetable based baby
food, or yogurt) or empty contents into a small amount of liquid (e.g., infant
formula, apple juice, or pediatric electrolyte solution). Food or liquid should
be at or below room temperature. The whole dose should be taken within 15
minutes of being sprinkled. The granules should not be chewed or crushed. The
dose should be taken 30 minutes before a meal. Do not store mixture for future
use.

Advise patient to immediately
report and seek care for diarrhea that does not improve. This may be a sign of Clostridium
difficile associated diarrhea [see WARNINGS AND PRECAUTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

In a 88/104-week carcinogenicity study in CD-1 mice,
rabeprazole at oral doses up to 100 mg/kg/day did not produce any increased
tumor occurrence. The highest tested dose produced a systemic exposure to
rabeprazole (AUC) of 1.40 μg•hr/mL, which is 1.6 times the human exposure
(plasma AUC0-∞ = 0.88 μg•hr/mL) at the recommended dose for GERD (20
mg/day). In a 28-week carcinogenicity study in p53+/-transgenic
mice, rabeprazole at oral doses of 20, 60, and 200 mg/kg/day did not cause an
increase in the incidence rates of tumors but produced gastric mucosal
hyperplasia at all doses. The systemic exposure to rabeprazole at 200 mg/kg/day
is about 17 to 24 times the human exposure at the recommended dose for GERD. In
a 104-week carcinogenicity study in Sprague-Dawley rats, males were treated
with oral doses of 5, 15, 30, and 60 mg/kg/day and females with 5, 15, 30, 60,
and 120 mg/kg/day. Rabeprazole produced gastric enterochromaffin-like (ECL)
cell hyperplasia in male and female rats and ECL cell carcinoid tumors in
female rats at all doses including the lowest tested dose. The lowest dose (5
mg/kg/day) produced a systemic exposure to rabeprazole (AUC) of about 0.1
μg•hr/mL, which is about 0.1 times the human exposure at the recommended
dose for GERD. In male rats, no treatment related tumors were observed at doses
up to 60 mg/kg/day producing a rabeprazole plasma exposure (AUC) of about 0.2
μg•hr/mL (0.2 times the human exposure at the recommended dose for GERD).

Rabeprazole was positive in the Ames test, the Chinese
hamster ovary cell (CHO/HGPRT) forward gene mutation test, and the mouse
lymphoma cell (L5178Y/TK+/–) forward gene mutation test. Its
demethylated-metabolite was also positive in the Ames test. Rabeprazole was
negative in the in vitro Chinese hamster lung cell chromosome aberration test,
the in vivo mouse micronucleus test, and the in vivo and ex vivo rat hepatocyte
unscheduled DNA synthesis (UDS) tests.

Rabeprazole at intravenous doses up to 30 mg/kg/day
(plasma AUC of 8.8 μg•hr/mL, about 10 times the human exposure at the
recommended dose for GERD) was found to have no effect on fertility and
reproductive performance of male and female rats.

Use In Specific Populations

Pregnancy

Pregnancy Category C

Risk Summary

There are no adequate and well-controlled studies with
ACIPHEX in pregnant women. No evidence of teratogenicity was seen in animal
reproduction studies with rabeprazole at 13 and 8 times the human exposure at
the recommended dose for GERD, in rats and rabbits, respectively (see Animal
Data). Changes in bone morphology were observed in offspring of rats
treated with oral doses of a different PPI through most of pregnancy and
lactation (see Animal Data). Because of these findings, ACIPHEX should
be used in pregnancy only if the potential benefit justifies the potential risk
to the fetus.

Animal Data

Embryo-fetal developmental studies have been performed in
rats at intravenous doses of rabeprazole up to 50 mg/kg/day (plasma AUC of 11.8
μg•hr/mL, about 13 times the human exposure at the recommended oral dose
for GERD) and rabbits at intravenous doses up to 30 mg/kg/day (plasma AUC of
7.3 μg•hr/mL, about 8 times the human exposure at the recommended oral
dose for GERD) and have revealed no evidence of harm to the fetus due to
rabeprazole.

Administration of rabeprazole to rats in late gestation
and during lactation at an oral dose of 400 mg/kg/day (about 195 times the
human oral dose based on mg/m²) resulted in decreases in body weight
gain of the pups.

A pre-and postnatal developmental toxicity study in rats
with additional endpoints to evaluate bone development was performed with a
different PPI at about 3.4 to 57 times an oral human dose on a body surface
area basis. Decreased femur length, width and thickness of cortical bone,
decreased thickness of the tibial growth plate, and minimal to mild bone marrow
hypocellularity were noted at doses of this PPI equal to or greater than 3.4
times an oral human dose on a body surface area basis. Physeal dysplasia in the
femur was also observed in offspring after in utero and lactational exposure to
the PPI at doses equal to or greater than 33.6 times an oral human dose on a
body surface area basis. Effects on maternal bone were observed in pregnant and
lactating rats in a pre-and postnatal toxicity study when the PPI was
administered at oral doses of 3.4 to 57 times an oral human dose on a body
surface area basis. When rats were dosed from gestational day 7 through weaning
on postnatal day 21, a statistically significant decrease in maternal femur
weight of up to 14% (as compared to placebo treatment) was observed at doses
equal to or greater than 33.6 times an oral human dose on a body surface area
basis.

Nursing Mothers

It is not known if ACIPHEX is excreted in human milk;
however, rabeprazole is present in rat milk. Because many drugs are excreted in
milk, caution should be exercised when ACIPHEX is administered to a nursing
woman.

Pediatric Use

Symptomatic GERD in Adolescent Patients Greater or Equal
to 12 Years of Age

In a multicenter, randomized, open-label, parallel-group
study, 111 adolescent patients 12 to 16 years of age with a clinical diagnosis
of symptomatic GERD, or suspected or endoscopically proven GERD, were
randomized and treated with either ACIPHEX 10 mg or ACIPHEX 20 mg once daily
for up to 8 weeks for the evaluation of safety and efficacy. The adverse event
profile in adolescent patients was similar to that of adults. The related
reported adverse reactions that occurred in ≥ 2% of patients were headache
(5.4%) and nausea (1.8%). There were no adverse reactions reported in these
studies that were not previously observed in adults.

GERD in Pediatric Patients 1 to 11 Years of Age

The use of ACIPHEX for treatment of GERD in pediatric
patients 1 to 11 years of age is supported by a randomized, multicenter,
double-blind clinical trial which evaluated two dose levels of rabeprazole in
127 pediatric patients with endoscopic and histologic evidence of GERD prior to
study treatment. Dosing was determined by body weight: Patients weighing 6.0 to
14.9 kg received either 5 or 10 mg and those weighing 15.0 kg or more received
10 or 20 mg of ACIPHEX Sprinkle daily. After 12 weeks of rabeprazole treatment,
81% of patients demonstrated esophageal mucosal healing on endoscopic
assessment. In patients who had esophageal mucosal healing at 12 weeks and elected
to continue for 24 more weeks of rabeprazole, 90% retained esophageal mucosal
healing at 36 weeks. No prespecified formal hypothesis testing for evaluation
of efficacy was conducted. The absence of a placebo group does not allow
assessment of sustained efficacy through 36 weeks. There were no adverse
reactions reported in this study that were not previously observed in
adolescents or adults.

Symptomatic GERD in Infants 1 to 11 Months of Age

Studies conducted do not support the use of ACIPHEX Sprinkle
for the treatment of GERD in pediatric patients younger than 1 year of age.

In a randomized, multicenter, placebo-controlled
withdrawal trial, infants 1 to 11 months of age with a clinical diagnosis of
symptomatic GERD, or suspected or endoscopically proven GERD, were treated up
to 8 weeks in two treatment periods. In the first treatment period
(open-label), 344 infants received 10 mg of ACIPHEX Sprinkle for up to 3 weeks.
Infants with clinical response were then eligible to enter the second treatment
period, which was double-blind and randomized. Two hundred sixty-eight infants were
randomized to receive either placebo or 5 mg or 10 mg ACIPHEX Sprinkle.

This study did not demonstrate efficacy based on
assessment of frequency of regurgitation and weight-for-age Z-score. Adverse
reactions that occurred in ≥ 5% of patients in any treatment group and
with a higher rate than placebo included pyrexia (7%) and increased serum
gastrin levels (5%). There were no adverse reactions reported in this study
that were not previously observed in adolescents and adults.

Use of ACIPHEX Sprinkle in neonates is strongly
discouraged at this time for the treatment of GERD, based on the risk of
prolonged acid suppression and lack of demonstrated safety and effectiveness in
neonates.

Based on population pharmacokinetic analysis, the median
(range) for the apparent clearance (CL/F) was 1.05 L/h (0.0543-3.44 L/h) in
neonates and 4.46 L/h (0.822-12.4 L/h) in patients 1 to 11 months of age
following once daily administration of oral ACIPHEX Sprinkle.

Geriatric Use

Of the total number of subjects in clinical studies of
ACIPHEX, 19% were 65 years and over, while 4% were 75 years and over. No
overall differences in safety or effectiveness were observed between these
subjects and younger subjects, and other reported clinical experience has not
identified differences in responses between the elderly and younger patients,
but greater sensitivity of some older individuals cannot be ruled out.

Gender

Duodenal ulcer and erosive esophagitis healing rates in
women are similar to those in men. Adverse reactions and laboratory test
abnormalities in women occurred at rates similar to those in men.

Last reviewed on RxList: 1/9/2015
This monograph has been modified to include the generic and brand name in many instances.